The aims of regenerative medicine are to restore healthy function to organs damaged by disease or aging. A major issue is the source of cells to be used in regenerative medicine. It is often thought to be desirable to use cells derived from the patient himself/herself, because this is hypothesized to avoid the need to administer drugs to suppress immune rejection of the transplanted cells. The possibility of using patient- specific cells in regenerative medicine was greatly expanded by the discovery of induced pluripotent stem cells (iPS cells). iPS cells can be derived from any somatic cell, but have the properties of embryonic stem cells. Like embryonic cells, they can be used to generate any cell of the body that may be needed in regenerative medicine. The eventual goal of these studies is to derive iPS cells from individual animals and implant the cells into the donor animal following the directed differentiation of the iPS cells to specific cell lineages. Before such studies are possible, appropriate in vitro investigations are needed. A major question concerns the potential impact of donor age. Most patients who would be candidates for this form of therapy would be older, or, at least, mature adults. Nonhuman primates (NHPs) offer several advantages for basic and preclinical studies of iPS cells and their differentiated progeny, including the role of donor age. These advantages include genetic relatedness to humans, and similarly developed central nervous systems. The common marmoset (Callithrix jacchus), as a small, easily handled NHP, has been extensively validated as a biomedical model. In this research, we address several basic questions that must be answered before cell transplantation studies commence in NHPs. We ask: (1) Does the age of the donor change the properties of the derived iPS cells, impairing their properties as pluripotent cells? Does differentiation occur normally, and do the cells survive and undergo further differentiation following implantation in immunodeficient mice? We will derive and characterize iPS cells from NHPs of three age groups. Following tests of pluripotency, we will assess the ability of each iPS cell line to differentiate to neural progenitor cells (NPCs). To provide a robut test of proper differentiation, we will transplant NPCs into the CNS of immunodeficient mice. (2) Does the age of the donor increase the probability of the existence of a differentiation-resistant subpopulation of cells that could represent a risk for teratoma development? We will examine if there is long-term continued proliferation of transplanted cells in the mouse CNS. It is expected that appropriate differentiation will have reduced the rate of proliferation to negligible levels oer the long term, irrespective of donor age. (3) Does the age of the donor affect the expected recognition of the iPSC-derived cells as self versus nonself by immune cells of the donor? It is expected that the cells from one individual donor will elicit a reaction in vitro with immune cells from unrelated individuals, but not with immune cells from the same individual; is this normal relationship maintained in iPSC-derived differentiated cells, irrespective of donor age? Collectively, these studies will enable more effective cell therapy to be proposed in future implementations of regenerative medicine. If the studies reveal age-related defects, strategies to correct such defects will be required. However, if iPS cells generated from older NHP donors function equivalently to those from younger donors in all respects, in vivo tests of autologous cell therapy will proceed in the NHP model. Future studies would involve the transplantation of differentiated cells derived from iPS cells back into the donor animal, in long-term tests of the therapeutic potential and safety of iPSC-derived cells. PUBLIC HEALTH RELEVANCE: Veterans are among the many US Citizens who may benefit from the application of regenerative medicine to the therapy of human disease. In the future, regenerative medicine may offer better regeneration of organs that have suffered damage from trauma in combat or other events, and better approaches to the therapy of degenerative diseases that impair function and shorten life in older Veterans. An important discovery for regenerative medicine is induced pluripotent stem (iPS) cells. iPS cells are like embryonic stem cells, yet can be derived from any adult cell, such as a skin cell. When iPS cells are derived from the skin cells of an individual patient, they should be able to be transplanted back to the same patient without rejection. Before this is applied to human patients, the properties of iPS cells must be thoroughly explored in suitable animal models, to make sure that autologous cell therapy is both safe and effective. For this purpose nonhuman primates are ideal, because of their relatedness to humans and their similar central nervous systems.